Abstract
Obesity and diabetes are linked to an increased prevalence of kidney disease. Endoplasmic reticulum stress has recently gained growing importance in the pathogenesis of obesity and diabetes-related kidney disease. Melatonin, is an important anti-obesogenic natural bioactive compound. Previously, our research group showed that the renoprotective effect of melatonin administration was associated with restoring mitochondrial fission/fusion balance and function in a rat model of diabesity-induced kidney injury. This study was carried out to further investigate whether melatonin could suppress renal endoplasmic reticulum (ER) stress response and the downstream unfolded protein response activation under obese and diabetic conditions. Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally supplemented either with melatonin (10 mg/kg body weight (BW)/day) (M–ZDF and M–ZL) or vehicle (C–ZDF and C–ZL) for 17 weeks. Western blot analysis of ER stress-related markers and renal morphology were assessed. Compared to C–ZL rats, higher ER stress response associated with impaired renal morphology was observed in C–ZDF rats. Melatonin supplementation alleviated renal ER stress response in ZDF rats, by decreasing glucose-regulated protein 78 (GRP78), phosphoinositol-requiring enzyme1α (IRE1α), and ATF6 levels but had no effect on phospho–protein kinase RNA–like endoplasmic reticulum kinase (PERK) level. In addition, melatonin supplementation also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins phospho–c–jun amino terminal kinase (JNK), Bax, and cleaved caspase-3, as well as by upregulation of B cell lymphoma (Bcl)-2 protein. These improvements were associated with renal structural recovery. Taken together, our findings revealed that melatonin play a renoprotective role, at least in part, by suppressing ER stress and related pro-apoptotic IRE1α/JNK signaling pathway.
Highlights
The protein expression of glucose-regulated protein 78 kDa (GRP78) was significantly higher in the C–Zücker diabetic fatty (ZDF) group compared with the C–ZL group (2.2-fold; p < 0.001; Figure 1a) and was found to be significantly decreased after melatonin supplementation in both ZDF (2.2-fold) and ZL (1.3-fold) groups, as compared to their control counterparts without supplementation (p < 0.01 and p < 0.05, respectively; Figure 1a)
The relative protein level of phospho–protein kinase RNA–like endoplasmic reticulum kinase (PERK) was significantly increased in C–ZFD group compared with C–ZL group (2.1-fold; p < 0.01; Figure 1b), the extent of this change was not attenuated in either ZDF or ZL groups with melatonin supplementation, as compared to their corresponding without supplementation (p > 0.05; Figure 1b)
The relative protein amount of phospho–inositol-requiring enzyme1α (IRE1α) and ATF6 were found to be significantly increased in the C–ZDF group compared with the C–ZL group (3.1-fold and 3.0-fold, respectively; p < 0.001; Figure 1c,d), and melatonin supplementation lowered their expression in ZDF group (4.5-fold and 4.1-fold, respectively) but not in ZL group, as compared with the respective control ZDF (p < 0.001 and p < 0.001, respectively) and ZL
Summary
At the initial stage of ER stress, a protective process termed unfolded protein response (UPR) is initiated in the ER, which is mediated by three transmembrane sensors, including protein kinase RNA–like endoplasmic reticulum kinase (PERK), activated transcription factor 6 (ATF–6) and inositol-requiring enzyme1α (IRE1α) [5]. Upon accumulation of unfolded proteins in the ER, GRP78 becomes dissociated from these transducers proteins, and UPR cascade is activated after dimerization and autophosphorylation of PERK and IRE1α, and regulated intramembrane proteolysis of ATF6. This response induced by UPR triggers the reduction in global protein synthesis, the degradation of misfolded or unfolded proteins, and the increase of protein chaperones synthesis, especially GRP78. One or more pro-apoptotic signaling pathways are known to contribute to cell death under prolonged or chronic activation of the three UPR pathways
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